17-alkynylandrosta-4, 6-diene-3, 17-diols, esters thereof and 19-nor compounds corresponding



United nt C resented $533122 cally, 17a-ethynylandrosta-4,-6-diene-3Q,l7/3-di0l or 17(3- 3,096,355 acetoxy-l7a-ethynylestra-4,6-dien-3fl-ol are allowed to re- 17 ALKYNYLANDROSTA-4,6-DIENE 3,17 DIOLS, act with acetic anhydride in pyridine at room temperature ESTERS THEREOF AND 19'N0R COMPOUNDS to yield 3,8acetoxy-17a-ethynylandroSta-4,6-dien-17fl-ol CORRESPONDHIG 1 317-d' 1'. to John S. Baran, Morton Grove, IlL, assignor to G. D. 5 ig i z zgg y Chem 1101 lace fig f f ggi 5 52532; i fi gffgff g Pg g g The compounds of this invention are useful as a result Cl i 1 2. 0 397,5 of their valuable pharmacological properties. They are,

for example, progestational agents which lack the potent The present invention is concerned with novel bisoxy- 10 anabolic and androgenic side effects typical of related genated steroids and, more particularly, with optionally PYIOI f }P esterified l7m alkynyl-4,6-diene-3[3,17,8-diols of-the andro- The {IWentlOIl W111 pp more fully from the examstane and estrane series, which are represented by the P Whlch follow- These @Xamples are Set forth y f y structural form l of illustration only and it will be understood that the incm 15 vention is not to be construed as limited in spirit or in OR scope by the details contamed therein, as many modificaalkynyn tions in materials and methods will be apparent from this disclosure to those skilled in the art. In these examples,

temperatures are given in degrees Centigrade C.).

Quantities of materials are expressed in .parts by weight unless otherwise noted.

Example-1 A mixture of 3 parts of 17a-ethynyl-IZB-hydroxyandrost-4-en-3-one, 6 parts of chloranil, 40 parts of tertiary-butyl alcohol, and 100 parts xylene is heated at reflux with stirring for about 5 hours. The resulting solution is cooled to room temperature and Washed with about 200 parts of 10% aqueous sodium hydroxide containing 10 parts of sodium sulfite. The organic layer is separated, washed with saturated aqueous sodium chloride, dried quickly over anhydrous sodium sulfate, then evaporated to dryness. The resulting residue is triturated with wherein R is hydrogen or a methyl radical, and R and 25 R" can be hydrogen or a lower alkanoyl group.

The lower alkanoyl groups encompassed by R and R are exemplified by formyl, 'acetyl, propionyl, butyryl, valeryl, caproyl, and the branched-chain isomers thereof.

The compounds of this invention can be conveniently manufactured by utilizing as starting materials the corresponding 3-keto-A compounds of the structural formula CH3 methanol to afiord 17u-ethynyl-17B-hydroxyandrosta-4,6-

0H dieu-3-one, melting at about 255260; [u] 99 alkynyl) (dioxane). This compound exhibits infrared maxima at about 2.93, 3.06, 3.38, 6.05, 6.18, 6.32, and 9.42 microns and also an ultraviolet absorption maximum at about 283 millimicrons with a molecular extinction coefficient of 40 about 26,000. This compound is represented by the structural formula 0H wherein R is hydrogen or a methyl radical. Dehydrogen- CH3 Ca ation of these A compounds, suitably by treatment with chloranil, affords the corresponding A substances, as is exemplified by the reaction of l7u-ethynyl-l7B-hydroxychloranil to produce 17u-ethynyl-l7fl-hydroxyandr0sta- 4,6-dien-3-one. Upon heating these A 3-ketones with a lower alkanoic acid anhydride in pyridine, the corresponding l7fi-alkanoates are obtained. For example, the aforementioned 17a ethynyl-l7B-hydroxyandrosta-4,6- dien-3-one is converted to 17,8-acetoxy-17a-ethynylandroandrost-4-en-3-one in xylene-tertiary-butyl alcohol with p Example 2 The substitution of 3.13 parts of 17fi-h3dIOXY 17oc-P1O- sta-4,6-dien-3-one by reaction with acetic anhydride in pynylanslrost'l'ena'one m the process of ExamPle 1 Pyridine These 3 4,s intermediates be com results in 17B-hydroxy l7a-propynylandrosta-4,6-dren-3- verted to the instant 3/8-hydroxy derivatives by means of Thls compound represented by the Structural any one of a variety of reducing agents, for example formula sodium borohydride, lithium aluminum hydride, and 0H3 lithium tri-(tertiary-butoxy) aluminum hydride. In the OH case of the 17 3-alkanoates, the latter reagent is preferred 0 in order to prevent hydrolysis of the ester group. This fi process is specifically illustrated by the reaction of 170ctoxy-l7a-ethynylandrosta-4,6-dien-3-o11e in tetrahydrofuran with lithium tri-(tertiary-butoxy) aluminum hydride to yield l7a-ethynylandrosta-4,6-diene-3fi,17,8-dio1 and 17B acetoxy-17a-ethynylandrosta-4,6-dien-3,B-ol, respectively Example 3 The instant 3,8-(lower alkanoy1)oxy compounds can A mixture of 2 parts of 17a-ethynyl-l7,8-hydrdxyandrobe produced by reaction of the corresponding 3B-alcohols st-a-4,6-dien-3-one, 20 parts of acetic anhydride, and 50 with a lower alkanoic acid anhydride in pyridine. Typiparts of pyridine is heated at reflux for about 2 hours,

then is cooled to about and diluted with water. The resulting aqueous mixture is extracted with ether, and the organic layer is separated, then washed successively with dilute hydrochloric acid, Water, and aqueous sodium bicarbonate. The washed solution is dried over anhydrous sodium sulfate, then evaporated to dryness. Crystallization of the resulting residue from ether-hexane aifords 17,6 acetoxy 17a ethynylandrosta-4,6-dien-3-one, M.P. about 145-146; [a] =-86 (chloroform). It is further characterized by infrared maxima at about 3.06, 3.38, 5.71, 6.00, 6.15, 6.30, 8.12 and 9.79 microns and also an ultraviolet maximum at about 282.5 millimicrons with a molecular extinction coefiicient of about 26,300. This compound is represented by the structural formula OCOCHa CH3 Example 4 By substituting 26 parts of propionic anhydride in the process of Example 3, 17a-ethynyl-l7,8-propionoxyandrosta-4,6-dien-3-one is obtained. This compound is represented by the structural formula CH; CH (30001120113 3 "05011 0 Example 5 By substituting 2.06 parts of 17,8-hydroxy-17ot-propynylandrosta-4,-6-dien-3-one and otherwise proceeding according to the processes of Example 3, l7fi-acetoxy-17a-propynylandrosta-4,6-dien-3-one is obtained. This compound is represented by the structural formula OCOCHa CH Example 6 228-230". It displays maxima in the ultraviolet at about 232, 238, and 246 millimicrons with molecular extinction coefiicients of about 21,000, 24,700, and 14,500, respec- The substitution of 1.04 parts of 17/9-hydroxy-17a-propynylandrosta-4,6-dien-3-one in the procedure of Example 6 results in 17a-propynylandrosta-4,6-diene-35,17/3- diol. This compound is represented by the structural formula om CH3 R Example 8 The substitution of 1.13 parts of 17,8-acetoxy-17a-ethynylandrosta-4,6-dien-3-one in the procedure of Example 6 results in an oil, which is crystallized from ether-pentane to yield 17p-acetoxy-17a-ethynylandrosta-4,6-dien-3fi-ol. This substance melts at about 138l40; [u] =143 (chloroform). It is further characterized by infrared maxima at about 2.80, 2.92, 3.05, 3.34, 5.78, 6.12, 8.03, 9.66, 9.80, and 11.66 microns, and also ultraviolet maxima at about 231, 238.5, and 246.5 millimicrons with molecular extinction coeflicients of about 22,400, 25,400, and 16,500, respectively. This compound is represented by the structural formula GH O CO CH3 CH3 i "CECE Example 9 By substituting 1.19 parts of 17a-ethynyl-17B-propionoxyandrosta-4,6-dien-3-one in the procedure of Example 6, 17a-ethynyl-17fi-propionoxyandrosta-4,6-dien-318-ol is obtained. This compound is represented by the struct ral formula 0 O O CHzCHa Example 10 The substitution of 1.19 parts of 17,8-acetoxy-17apropynylandrosta-4,6-dien-3-one in the procedure of Example 6 results in 17;3-acetoxy-17u-propynylandrosta-4,6

C 0 CH9 CH A ozoom Example 11 A mixture of one part of 17oc-ethynylandrosta-4,6 diene-3fl,17fi-diol, 4 parts of acetic anhydride, and 10 parts of pyridine is stored at room temperature for about 18 hours, then is cooled to about 0. Dilution with water results in precipitation of the product, which is collected by filtration, Washed on the filter with Water, and dried. Recrystallization of this crude product from ether-hexane affords pure 3fi-acetoxy-17a-ethynylandrosta-4,6-dien- 17,8-01, M.P. about 129-131; [a] =l62.5 (chloroform). It displays maxima in the infrared at about 2.73, 3.01, 3.37, 5.75, 6.05, 7.93, 9.55, 9.77, and 10.38 microns, and also ultraviolet maxima at about 23-1, 238, and 246' millimicrons with molecular extinction coefficients of about 24,800, 27,400, and 16,400, respectively. This compound is represented by the structural formula OH 3 L OHsOOO- Example 12 A mixture of one part of 17a-ethynylandrosta-4,6- diene-3fi,17,B-diol, one part of propionic anhydride, and 3 parts of pyridine is allowed to stand at room temperature for about hours, then is cooled to about 0 and diluted with water. The resulting aqueous mixture is extracted with ether, and the organic layer is separated, washed successively with dilute hydrochloric acid, water, and aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, and evaporated to dryness. The residual material is crystallized from ether-hexane to produce pure 17a ethynyl 3t? propionoxyandrosta 4,6 dien 17/3- 01, MP. about 117-118; [a] '==l63 (chloroform). Its infrared absorption spectrum displays maxima at about 2.81, 3.05, 3.42, 5.82, 6.11, 6.23, 8.45, 9.29, 9.45, and 9.92 microns, while its ultraviolet absorption spectrum is characterized by maxima at about 231, 238, and 246 millimicrons with molecular extinction coefficients of about 24,200, 26,800, and 17,000, respectively. This compound is represented by the structural formula OH C CHgCHzCOO- Example 13 By substituting 1.04 parts of 17a-propynylandrosta-4,6- diene-3B,17,8-diol and otherwise proceeding according to the processes of Example 11, 35-acetoxy-17a-propynyl 6 androsta-4,-6-dien-17,B-ol is obtained. This compound is represented by the structural formula OH 0H3 --oEooH3 CHaCOO Example 14 The substitution of 1.14 parts of 17fi-acetoxy-17aethynylandrosta-4,6-dien-3/3-ol in the procedure of Example 11 results in 17a-ethynylandrosta-4,6-diene-3B,17B- diol 3,17-diacetate, M.P. about -166. This compound is represented by the struotural formula OOOGHs Example 1 5 The substitution of 1.17 parts of 17a-ethynyl-17B-propionoxyandrosta-4,6-dien-3fl-ol in the procedure of Example 12 results in 17a-ethynylandrosta-4,6-dime-3,8,17B- diol 3,17-dipropionate. This compound is represented by the structural formula CHsCOO- 0 o 0 onion, CH3 ---ozon Example 16 By substituting 1.05 parts of .-17fi-acetoxy-l7a-propynylandrosta-4,6-dien-3p-'ol in the 1 process of Example 11, l7a-propynylandrosta-4,6-diene 3p,17B-diol 3,17-diaoetate is obtained. This compound is represented by the structural formula 0 o 0 CH3 ---ozoon,

OHaCOO- Example 17 7 also ultraviolet absorption maxima at about 233, 239.5, and 248 rnillirnicrons with molecular extinction coefiicients of about 22,600, 24,500, and 15,700, respectively. This compound is represented by the structural formula C O CH:

Example 18 By substituting 4.8 parts of 17oc-bl1tYnYl-17B-P1OPiOI1- 0xyestra-4,6-dien-3-one and otherwise proceeding according to the processes of Example 17, 17a butynyl-17fipropionoxyestra-4,6-dien-3fl-ol is obtained. This compound is represented by the structural formula Example 19 p The substitution of 1.09 parts of l7fi-acetoxy-17aethynylestra-4,6-dicn-3fl-ol in the procedure of Example 11 results in 17a-ethynylestra-4,6-diene-3 3,17,6-diol 3,17- diacet-ate, which melts at about 188490"; [a] =165. It exhibits infrared maxima at about 3.01, 3.37, 5.73, 6.05, 6.22, 9.70, 10.26, and 11.33 microns. This compound is represented by the structural formula 0 CO CH3 I "CECE H OHsCOO- Example 20 The substitution of 1.09 parts of l7a-butynyl-17fi-propionoxyestra-4,6-dien-3B-ol and 5.1 parts of propionic anhydride in the procedure of Example 11 results in 170:- butynylestra 4,6 diene 3 5,17 ,8 diol 3,17 -dipropionate.

Ihe substitution of 2.86 parts of 17a-ethnyl-17flhydroxyestra-4-en-3-one in the procedure of Example 1 8 results in -ethynyl-17fi-hydroxyestra-4,6-dien-34one. This compound is represented by the structural formula :'---ozon Example 22 The substitution of 0.95 part of 17a-ethynyl-17/9-hydroxyestra-4,6-dien-3-one in the procedure of Example 6 results in l7a-ethynylestra-4,6-diene-3p,17 8-diol. This compound is represented by the structural formula Example 23 'By substituting 0.95 part of 17a-ethynylestra-4,6-diene- 35,17,6-diol and otherwise proceeding according to the processes of Example 11, 3fi-acetoxy-17a-ethynylestra- 4,6-dien-17/3-ol is obtained. This compound is represented by the structural formula OHaCOO- What is claimed is: 1. A compound of the structural formula p j "(lower alkynyl) wherein R is selected from the group consisting of hydrogen and a methyl radical, and R and R are selected from the group consisting of hydrogen and lower alkanoyl radicals.

2. A compound of the structural formula 0 0 0 (lower alkyl) 0H 3. A compound of the structural formula diacetate.

8. 17a ethynylandrosta 4,6 diene-3B,17fl-dio1-3,17-

O C 0 (lower alkyl) '---(10wer alkynyl) 5 diacetate.

4. 17u-ethyny1andr0sta-4,6-diene-3 8,I7B-diol.

5. 17,8-acetoxy-17a-ethnylandrosta-4,6-dien-3fi-o1.

6. 3B-acetoxy-17a-ethynylandrosta-4,6-dien-17,8-01.

7. 17u-ethyny1-3fi-propionoxyandrostal,6-dien-1718-01.

10. 170: ethynylestra 4,6 diene 3fl,176 di01-3,17-

References Cited in the file of this patent UNITED STATES PATENTS Miesher et a1. Feb. 16, 1943 Colton July 15, 1958 Agnello et a1. Apr. 14, 1959 Cohen July 26, 1960 OTHER REFERENCES 15 Chemical and Engineering News, September 16, 1957,

pages 66-67. 

1. A COMPOUND OF THE STRUCTURAL FORMULA 